Tisagenlecleucel (CTL019) FDA Advisory Committee Briefing Document Novartis 12-Jul-2017 ONCOLOGIC DRUGS ADVISORY COMMITTEE BRIEFING DOCUMENT Tisagenlecleucel (CTL019) for the TREATMENT OF PEDIATRIC AND YOUNG ADULT PATIENTS WITH RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION Page 1 Tisagenlecleucel (CTL019) FDA Advisory Committee Briefing Document Novartis 12-Jul-2017 Table of contents Table of contents .................................................................................................................2 List of tables ........................................................................................................................4 List of figures ......................................................................................................................6 List of abbreviations ............................................................................................................8 1 Executive summary ...........................................................................................................10 1.1 Tisagenlecleucel (CTL019) ...................................................................................10 1.1.1 Targeted indication................................................................................10 1.1.2 Unmet medical need for r/r B-cell ALL................................................10 1.1.3 Mechanism of action.............................................................................11 1.1.4 Manufacturing process ..........................................................................11 1.2 Pediatric and young adult r/r B-cell ALL clinical development program .............11 1.2.1 Trial designs and conduct......................................................................13 1.3 Efficacy of tisagenlecleucel in B-cell ALL ...........................................................13 1.3.1 Interim analysis – Study B2202 ............................................................15 1.3.2 Final analysis of ORR in patients treated with US-manufactured product – Study B2202..........................................................................15 1.4 Safety of tisagenlecleucel in B-cell ALL...............................................................17 1.5 Benefit-risk assessment for tisagenlecleucel in B-cell ALL..................................22 2 Background information....................................................................................................25 2.1 Epidemiology and outcome ...................................................................................25 2.2 Current treatment options for r/r B-cell ALL ........................................................25 2.2.1 Relapsed/refractory ALL ......................................................................25 2.2.2 Outcomes for patients with r/r B-cell ALL...........................................25 2.3 Rationale for the development of tisagenlecleucel in B-cell ALL ........................27 2.3.1 Mechanism of action.............................................................................27 2.4 Manufacturing process...........................................................................................29 2.4.1 Controlling key tisagenlecleucel product attributes (step 5 - quality assessment)............................................................................................32 2.4.2 Lentiviral vector ....................................................................................32 2.4.3 Chain of identity....................................................................................33 2.4.4 Correlation between characteristics of engineered product and clinical outcomes...................................................................................33 2.5 Clinical development program ..............................................................................35 3 Clinical pharmacology.......................................................................................................37 3.1 Cellular kinetics: general characteristics ...............................................................37 3.1.1 Cellular kinetics in peripheral blood .....................................................38 Page 2 Tisagenlecleucel (CTL019) FDA Advisory Committee Briefing Document Novartis 12-Jul-2017 3.1.2 Cellular kinetics in bone marrow aspirates ...........................................38 3.1.3 Factors influencing cellular kinetics .....................................................39 3.2 Dose-cellular kinetics ............................................................................................39 3.3 Relationship between manufacturing release characteristics and cellular kinetics...................................................................................................................39 4 Key aspects of the clinical development program.............................................................42 4.1 Regulatory consultations .......................................................................................42 4.2 Dose-selection rationale.........................................................................................42 4.3 General methodological considerations.................................................................43 4.3.1 Trial design and conduct .......................................................................43 4.3.2 Efficacy endpoints and statistical methodology....................................46 4.3.3 Adequacy of safety evaluations ............................................................48 5 Efficacy of tisagenlecleucel in B-cell ALL .......................................................................49 5.1 Efficacy results in supportive Studies B2101J and B2205J ..................................49 5.1.1 Patient populations – Studies B2101J and B2205J...............................49 5.1.2 Magnitude of treatment effect – Studies B2101J and B2205J..............50 5.2 Pivotal Study B2202..............................................................................................52 5.2.1 Disposition of patients – Study B2202..................................................52 5.2.2 Dose administration – Study B2202 .....................................................53 5.2.3 Analysis sets – Study B2202.................................................................53 5.2.4 Patient population – Study B2202.........................................................54 5.2.5 Interim analysis – Study B2202 ............................................................55 5.2.6 Updated primary efficacy endpoint: ORR – Study B2202 ...................55 5.2.7 Updated secondary efficacy endpoints – Study B2202.........................57 5.3 Dose-response analyses .........................................................................................62 5.4 Long-term data.......................................................................................................64 5.4.1 Persistence of efficacy and long-term benefit.......................................64 6 Safety of tisagenlecleucel in B-cell ALL ..........................................................................65 6.1 Safety population ...................................................................................................65 6.2 Patient exposure – Studies B2202 and B2205J .....................................................66 6.2.1 Lymphodepleting chemotherapy – Studies B2202 and B2205J ...........66 6.2.2 Tisagenlecleucel infusion – Studies B2202 and B2205J ......................67 6.3 Adverse events – Studies B2202 and B2205J .......................................................67 6.3.1 Frequent adverse events – Studies B2202 and B2205J.........................67 6.3.2 Deaths and other serious or clinically significant adverse events – Studies B2202 and B2205J ...................................................................74 6.4 Clinical chemistry and hematology – Studies B2202 and B2205J........................86 Page 3 Tisagenlecleucel (CTL019) FDA Advisory Committee Briefing Document Novartis 12-Jul-2017 6.4.1 Clinical chemistry abnormalities – Studies B2202 and B2205J ...........86 6.4.2 Hematology abnormalities – Studies B2202 and B2205J.....................86 6.5 Patient-reported outcome data – Study B2202 ......................................................87 6.6 Adverse events – Study B2101J ............................................................................88 6.6.1 Frequent adverse events – Study B2101J..............................................88 6.6.2 Deaths – Study B2101J .........................................................................90 6.7 Deaths in ongoing adult ALL studies ....................................................................90 6.8 Dose-safety and exposure-safety analyses.............................................................91 6.8.1 Dose-safety analyses .............................................................................91 6.8.2 Exposure-safety analyses ......................................................................93 6.9 Immunogenicity.....................................................................................................93 7 Measures to lessen or manage adverse events post-approval............................................94 8 Benefit-risk evaluation ......................................................................................................97 8.1