Model-based optimization of rituximab dosing regimen in follicular non-hodgkin lymphoma

Transcription

1 Model-based optimization of rituximab dosing regimen in follicular non-hodgkin lymphoma D. Ternant, E. Hénin, G. Cartron, M. Tod, G. Paintaud, P. Girard

2 Introduction Objectives Introduction Rituximab in follicular lymphoma Rituximab : Monoclonal antibody targeted against human CD20 Large variability of concentration-effect relationship due to: Pharmacokinetic variability : efficacy for concentrations FCGR3A polymorphism: Progression-free survival () FCGR3A-VV > F carriers (Igarashi et al. 2002) Proportions VV (15%) Fx (85%) (Lejeune et al. 2009) Cartron,

3 Introduction Objectives Introduction Initial dosing regimen : induction treatment by 4 weekly 375 mg/m 2 injections number of injections, maintenance treatment: Progression-free survival R-CHOP + R maintenance R-CHOP + Observation van Oers,

4 Introduction Objectives Introduction The dosing regimen may be optimized: Increasing infusion dose Adjusting dosing regimen according to FCGR3A genotype But not confirmed by specific studies Clinical trial simulation But No PK-PD study of rituximab in FL 4

5 Introduction Objectives Model Building Objectives Build and evaluate a dose efficacy model of rituximab in follicular lymphoma Using data from literature Considering FCGR3A genotype Simulate dose efficacy relationship for several dosing regimens 5

6 Objectives Model building Model building Data Berinstein, 1998 McLaughlin, 1998 Weng, 2004 Pivotal study graphical extraction Model Median rituximab concentrations VV, Fx Estimation 2 compartment model Median PK parameters Estimation PD parameters Estimation PD parameters for FCGR3A Time-to-event model 6

7 Objectives Model building Model building Data Berinstein, 1998 McLaughlin, 1998 Weng, 2004 Pivotal study graphical extraction Model Median rituximab concentrations VV, Fx Estimation 2 compartment model Median PK parameters Estimation PD parameters Estimation PD parameters for FCGR3A Time-to-event model 7

8 Objectives Model building Pharmacokinetic model Median concentrations of Berinstein et al. 2-compartment model Median PK parameters Winnonlin Professional 4.1 RTX concentration Berinstein, 1998 Vc = 2.4 L CLc = L/h Vp = 3.7 L CLp = L/h Obs (T) Pred (T) Time (hours) 8

9 Objectives Model building Time-to-event model Data Berinstein, 1998 McLaughlin, 1998 Weng, 2004 Pivotal study graphical extraction Model Median rituximab concentrations VV, Fx 2 compartment model Median PK parameters Estimation PD parameters Estimation PD parameters for FCGR3A Time-to-event simulation model 9

10 Objectives Model building Time-to-event model ( t) = exp( ' * t) ( ) & Cm * = * ( $ max 1 ' ) ) % Cm50 + Cm Cm t n ' t = AUC t n t n ' t ' t = + t t n C t n #! " (, ) ' t d, λ : hazard function λ max : maximum hazard (no rituximab efficacy) Cm : mean-time concentration Cm 50 : Cm leading to 50% of λ max γ : shape factor 10

11 Objectives Model building Time-to-event model Time-to-event model: parameter estimation Cm 50, γ: estimated Median pharmacokinetics (Cm, Berinstein, 1998 ) (McLaughlin, 1998 ) McLaughlin, 1998 Progression-free survival λ max = 0.16 month -1 Cm 50 = 35.1 mg/l γ = Time (months) 11

12 Objectives Model building Influence of FCGR3A Data Berinstein, 1998 McLaughlin, 1998 Weng, 2004 graphical extraction Model Median rituximab concentrations VV, Fx Estimation Median concentrations 2 compartment model Estimation λ max, Cm 50, γ Estimation Cm 50,VV,Cm 50,Fx γ VV, γ Fx Time-to-event simulation model 12

13 Objectives Model building Influence of FCGR3A γ values for VV and Fx were fixed: γ Fx = γ = 0.5. γ VV = 2 Estimation of Cm 50,VV and Cm 50,Fx VV and Fx (24 months) Weng, Cm 50,VV = 7.9 mg/l Cm 50,Fx = 78.9 mg/l HR Fx/VV = 2.5 McLaughlin, 1998: # # Fx, M 24 VV, M 24 = # ˆ = # ˆ M 24 M 24 " HR HR 1! 0.85 Fx/ VV 1! 0.15 Fx/ VV # # Fx, M 24 VV, M 24 = # ˆ = # ˆ M 24 M 24 " HR HR 1! 0.85 Fx / VV VV (15%) HR Fx/VV = 2.5 1! 0.15 Fx / VV Overall Fx (85%) Then calculation of Cm 50,VV and Cm 50,Fx by solving the equations: 24 months TTP genotype (24M) = f (Cm 50,genotype ) 13

14 Objectives Model building Simulation model Data Berinstein, 1998 McLaughlin, 1998 Weng, 2004 graphical extraction Model Median rituximab concentrations VV, Fx Estimation Median concentrations 2 compartment model Estimation λ max, Cm 50, γ Estimation Cm 50,VV,Cm 50,Fx γ VV, γ Fx Ng, 2005 Population PK parameters Time-to-event simulation model ω Cm50 = 50% 14

15 Objectives Model building Simulation model Simulation of published studies Number of patients = eligible patients of the study Number of simulations = 500 Evaluation: visual predictive checks (VPC) observed model-predicted (90% confidence interval) Trial simulator II.2, S-Plus

16 Model Building Dose alteration Evaluation van Oers, 2006 Cartron, 2002 graphical extraction CHOP R-CHOP + obs R-CHOP + maint Individual TTP VV, Fx TTE simulation model TTE simulation model Internal evaluation (Pivotal) (Weng) Analysis of sensitivity (Pivotal) (Weng) External evaluation (van Oers) (Cartron) 16

17 Model Building Dose alteration Internal evaluation van Oers, 2006 Cartron, 2002 graphical extraction CHOP R-CHOP + obs R-CHOP + maint Individual TTP VV, Fx TTE simulation model TTE simulation model Internal evaluation (Pivotal) (Weng) Analysis of sensitivity (Pivotal) (Weng) External evaluation (van Oers) (Cartron) 17

18 Model Building Dose alteration Internal evaluation Pivotal study (McLaughlin et al. 1998) * 375 mg/m 2 /week confidence interval 90% 500 simulations C 95 C 50 C observed Time (months) 18

19 Model Building Dose alteration Internal evaluation Influence of FCGR3A genotype : Weng et al M24 4 * 375 mg/m 2 /week 0.6 VV Progression free survival Fx Time (months) 19

20 Model Building Dose alteration External evaluation van Oers, 2006 Cartron, 2002 graphical extraction CHOP R-CHOP + obs R-CHOP + maint Individual TTP VV, Fx TTE simulation model TTE simulation model Internal evaluation (Pivotal) (Weng) Analysis of sensitivity (Pivotal) (Weng) External evaluation (van Oers) (Cartron) 20

21 Model Building Dose alteration External evaluation Studies Van Oers et al.2006 : of relapsed/resistent FL patients treated with: R-CHOP R-CHOP + rituximab maintenance (375 mg/m 2 every 3 months) Cartron et al., 2002 : of first-line FL VV et Fx patients (rituximab 4 x 375 mg/m 2 ) 21

22 Model Building Dose alteration External evaluation Van Oers et al. R-CHOP Without maintenance R-CHOP With maintenance 6 * 375 mg/m 2 /21d 6 * 375 mg/m 2 /21d mg/m 2 /3months 1.0 M M progression free survival progression free survival Time (months) Time (months) 22

23 Model Building Dose alteration Cartron et al., x 375 mg/m 2 /week. 1.0 M VV Progression free survival Fx Time(months) 23

24 Model Building Dose alteration Conclusion: model Satisfactory description of rituximab within M24 With and without rituximab maintenance For both FCGR3A genotypes (M24) : metrics 24

25 Model Evaluation Dose alteration Conclusion Dosing regimen alteration Rituximab monotherapy (Cartron et al. 2002) : Fx vs. VV 4 weekly doses + maintenance every 2 months Dose alteration Induction : 375, 750, 1500, 2250 mg/m 2 Maintenance : 375, 750, 1500, 2250 mg/m 2 25

26 Dose alteration Conclusion Conclusion and perspectives Main benefit : increase of maintenance dose of Fx never reach of VV Perspectives Improvement of the model : Tumor burden, stage of disease alteration of induction dose and schedule Confirmation by clinical trials 26

27 References Berinstein NL, Grillo-Lopez AJ, White CA, et al. Association of serum Rituximab (IDEC-C2B8) concentration and antitumor response in the treatment of recurrent low-grade or follicular non-hodgkin's lymphoma. Ann Oncol. 1998; 9: Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-cd20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002; 99: Lejeune J, Thibault G, Ternant D, et al. Evidence for linkage disequilibrium between Fcgamma RIIIa-V158F and Fcgamma RIIa-H131R polymorphisms in white patients, and for an Fcgamma RIIIa-restricted influence on the response to therapeutic antibodies. J Clin Oncol. 2008; 26: ; author reply Epub 2008 Oct 27. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma. J Clin Oncol McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998; 16: Ng CM, Bruno R, Combs D, et al. Population pharmacokinetics of rituximab (anti-cd20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial. J Clin Pharmacol. 2005; 45: van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006; 108:

28 Objectives Model building Time-to-event model Parameter estimation λ max : fixed Rituximab (R) combined with chemotherapy (X) λ max = λ X R alone Effects for R and X are assumed to be independent HR 0/R = HR X/R-X λ max = λ R x HR X/R-X HR X/R-X : Marcus et al.,

29 Model Building Dose alteration Internal evaluation Sensitivity analysis (fixed parameters) A 0.6 McLaughlin, 1998 Weng, B 0 10% 50% 150% Cm50 max VV VV 29

30 Mean-time concentration AUC(t) C(t) 30

31 Model parameters AUC(t) Cm(t) C(t) 31